DiOHF Protects Against Doxorubicin-Induced Cardiotoxicity Through ERK1 Signaling Pathway.

Danqi Chang,Yanggan Wang,Hang Li,Cheng Qian

doi:10.3389/fphar.2019.01081

Danqi Chang, Yanggan Wang + Show 2 more

Open Access

https://doi.org/10.3389/fphar.2019.01081

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Abstract

Doxorubicin (DOX) is an effective anticancer agent. Its clinical use is, however, limited due to its detrimental side effects, especially the cardiotoxicity caused by ROS, mitochondrial dysfunction and apoptosis. 3’,4’-dihydroxyflavonol (DiOHF) is a recently developed potent synthetic flavonoid which has been reported to exert anti-oxidative activity in myocardial ischemia–reperfusion injury and maintain the normal mitochondrial function. The aim of this study was to explore the protective effects of DiOHF on the DOX-induced cardiotoxicity. We established DOX-induced cardiotoxicity in H9C2 cells by incubation with 1 μM DOX and in BALB/c mice by DOX injection. DiOHF effectively prevented and reversed the DOX-induced cardiotoxicity, including ROS production, mitochondrial dysfunction, and apoptosis. The DOX-induced cardiotoxicity was accompanied by ERK1/2 activation and abolished by the silence of ERK1, rather than ERK2. Furthermore, DOX treatment in mice induced an increase in serum CK-MB level and myocardial fibrosis with a reduction in left ventricular (LV) function. These detrimental effects were blunted by DiOHF administration. Conclusion: DiOHF suppresses and reverses the DOX-induced cardiotoxicity by inhibiting ROS release, stabilizing mitochondrial function and reducing apoptosis through activation of the ERK1 signaling.

Highlights

Doxorubicin (DOX), an anthracycline antibiotic, has been widely used as a chemotherapeutic agent for the treatment of various cancers in human (Todaro et al, 2013)
Primary antibodies against cleaved-caspase-3, Bid, and Bcl-2 were obtained from Abclonal (Wuhan, China), and ERK1/2, p-ERK1/2, and GAPDH were obtained from Cell Signaling Technology (Beverly, MA, USA)
Whether DiOHF can protect against the DOXinduced cardiotoxicity has not been reported

Summary

Introduction

Doxorubicin (DOX), an anthracycline antibiotic, has been widely used as a chemotherapeutic agent for the treatment of various cancers in human (Todaro et al, 2013). Previous studies have found that DOX-induced cardiotoxicity involves the production of reactive oxygen species (ROS) (Xu et al, 2001; Menna et al, 2012; He et al, 2018), mitochondrial dysfunction (Dolinsky, 2017; Xia et al, 2017; Gorini and De Angelis, 2018; Govender et al, 2018; He et al, 2018; Liu et al, 2018), and apoptosis (Wang et al, 2014; Mantawy et al, 2017; Chen et al, 2018; Tang et al, 2018), the underlying mechanisms are unknown. Most evidence indicate that the major mechanism of DOX-induced cardiotoxicity involves ROS production (Xu et al, 2001; Menna et al, 2012; He et al, 2018). The semiquinone is unstable, and can provoke injury to the DNA or can be turned into quinone, which

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